CacyBP/SIP inhibits the migration and invasion behaviors of glioblastoma cells through activating Siah1 mediated ubiquitination and degradation of cytoplasmic p27

Yan, Shiwei; Li, Aimin; Liu, Yuguang

doi:10.1002/cbin.10889

Cited by 20 publications

(26 citation statements)

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“…Phosphorylation modifications predominantly mediate the regulation of P27 Kip1 's cellular localization, among which Ser10 phosphorylation promotes P27 Kip1 nuclear export via CRM1 protein 34, 43, and Thr157 or Thr198 phosphorylation, in a less common way, impairs P27 Kip1 nuclear import under serum stimulation 44. As P27 Kip1 is a known downstream target of both CACYBP and RNF41, a previous study has described that CACYBP aids in the degradation of cytoplasmic P27 Kip1 by Siah1 45, and RNF41 reduces the level of cytoplasmic P27 Kip1 via suppression of ERBB3-Akt signaling 46, thus causing effects on the migration and invasion abilities of glioma cells. Apart from increasing cellular migratory activity, cytoplasmic P27 Kip1 has also been reported to suppress apoptosis in breast cancer 47 and enhance proliferation in trophoblast cells 48.…”

Section: Discussionmentioning

confidence: 99%

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

Lian¹,

Huang²,

Zhang³

et al. 2019

Theranostics

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Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.Methods: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation. Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP. The regulatory mechanism of RNF41-CACYBP signaling axis on P27Kip1 was investigated by western blotting and immunofluorescence.Results: CACYBP was highly expressed and associated with poor prognosis in HCC. CACYBP expression was required for HCC cell growth in vitro and in vivo. Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels. RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome- and lysosome-dependent pathways. In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression. Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27Kip1 and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon. CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells. P27Kip1-S10D but not P27Kip1-S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.Conclusion: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.

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Section: Discussionmentioning

confidence: 99%

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

Lian¹,

Huang²,

Zhang³

et al. 2019

Theranostics

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“…Besides, CacyBP/SIP associates with Siah-1, Skp1, and TBL1 to form a ubiquitin ligase complex called SCF T BL1 -catenin by ubiquitination [10]. Recently, it was proposed that CacyBP/SIP could promote the interaction between Siah1 and cytoplasmic p27, which in turn increases the ubiquitination and degradation of cytoplasmic p27 [20]. In this study we showed that CacyBP/SIP interacted with Mdm2 to promote the ubiquitination of mutant Transcription factor p53 is reported to be activated by diverse genotoxic and cytotoxic stresses [21].…”

Section: Discussionmentioning

confidence: 99%

CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells

Qian

Tang

Wang

et al. 2021

neo

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Our previous studies have illustrated that CacyBP/SIP (Calcyclin-binding protein or Siah-1-interacting protein) promoted the proliferation of glioma cells. However, the possible mechanism still needs to be clarified. In the current study, we aimed to uncover the potential mechanism of CacyBP/SIP in regulating glioma cell proliferation. We found that CacyBP/SIP decreased the protein level of p53, but not the mRNA level of p53 in p53 mutant U251 cell line, whereas, in p53 wild-type U87 cell line, CacyBP/SIP neither promoted its proliferation nor regulated the changes of p53 p rotein. Further investigation indicated that CacyBP/SIP interacted with p53 and Mdm2 (Mouse double minute 2) to promote p53 ubiquitination and subsequent proteasome-mediated degradation in U251. Moreover, in the presence of Mdm2, CacyBP/SIP boosted the ubiquitination of p53 in a dose-dependent manner. On the contrary, inhibition of Mdm2 activity significantly increased the stability of p53. Finally, we found that the protein level of CacyBP/SIP and p53 is inversely correlated in p53 mutant human glioma tissues. These observations suggest an underlying mechanism that CacyBP/SIP promotes the degradation of p53 by enhancing Mdm2 E3 ligase activity, which reveals a novel pathway for the regulation of mutant p53 and provides a new therapeutic approach to target t he CacyBP/SIP-induced glioma cell proliferation. Key words: CacyBP/SIP; p53; Mdm2; glioma; tumorigenesis Glioma is the most common type of brain tumor with the median survival time of only 12 to 15 months, despite the significant improvements in neurosurgery, radiotherapy and chemotherapy [1, 2]. The poor prognosis of glioma is largely attributed to the rapid growth and invasive/migratory nature of glioma cells. Therefore, an understanding of the mechanisms underlying glioma development and progression is critical to discover specific molecular targets that could be served as effective methods for glioma treatment.

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“…Ubiquitinated substrates identified to date include p27 and β-catenin (5,19). Ubiquitinated substrates identified to date include p27 and β-catenin (5,19).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis of Cacybp‐associated proteins using human glioma databases

Xuan¹,

Gao²,

Jin³

et al. 2019

IUBMB Life

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The ubiquitin‐proteasome system is the primary cellular pathway for protein degradation, mediating 80% of intracellular protein degradation. Because of the widespread presence of ubiquitin‐modified protein substrates, ubiquitination can regulate a variety of cellular activities including cell proliferation, apoptosis, autophagy, endocytosis, DNA damage repair, and immune responses. With the continuous generation of genomics data in recent years it has become particularly important to analyze these data effectively and reasonably. Cacybp forms a complex with the E3 ubiquitinated ligase Siah1 to participate in ubiquitination. We analyzed Cacybp‐associated genes using the Gene Expression Omnibus (GEO) and CGGA (Chinese Glioma Genome Atlas) databases and identified 121 differentially expressed genes (DEGs), of which 46 were downregulated and 75 were upregulated. The biological processes, molecular functions, and protein–protein interaction (PPI) network of differential genes were analyzed by Cytoscape software and STRING software. We found no difference in Cacybp expression among different grades of gliomas and there was no significant association between the expression level of Cacybp and the prognosis of patients with glioma in LGG and GBM. © 2019 IUBMB Life, 1–8, 2019

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CacyBP/SIP inhibits the migration and invasion behaviors of glioblastoma cells through activating Siah1 mediated ubiquitination and degradation of cytoplasmic p27

Cited by 20 publications

References 45 publications

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells

Bioinformatic analysis of Cacybp‐associated proteins using human glioma databases

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CacyBP/SIP inhibits the migration and invasion behaviors of glioblastoma cells through activating Siah1 mediated ubiquitination and degradation of cytoplasmic p27

Cited by 20 publications

References 45 publications

CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells

Bioinformatic analysis of Cacybp‐associated proteins using human glioma databases

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CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation